Medicament dispenser

ABSTRACT

A dispenser for dispensing a medicament that includes a canister for housing the medicament and a fluid propellant therefor and a drug-dispensing valve wherein one or more of the internal surfaces of the canister and/or valve includes a fluorinated coating prepared from plasma polymerisation of one or more fluorinated monomers selected from the group consisting of CH 2 FCF 3  and C 3 F 6  is disclosed.

RELATED APPLICATION

The present application claims priority from UK patent application No.0125380.6 filed on 23 Oct. 2001, the entire content of which is herebyincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a dispenser for a metered dose inhaler.More especially, the invention relates to a dispenser for a metered doseinhaler for consistently dispensing a prescribed dose of medicament.

BACKGROUND OF THE INVENTION

Drugs for treating respiratory and nasal disorders are frequentlyadministered in aerosol formulations through the mouth or nose. Onewidely used method for dispensing such aerosol drug formulationsinvolves formulating the drug as a suspension or a solution in aliquefied gas propellant. The suspension/solution is stored in a sealedcanister capable of withstanding the pressure required to maintain thepropellant as a liquid. The suspension/solution is dispersed byactivation of a dose-metering valve affixed to the canister.

A metering valve generally comprises a metering chamber, which is of aset volume and is designed to administer per actuation an accuratepredetermined dose of medicament. As the suspension/solution is forcedfrom the metering chamber through the valve stem by the high vapourpressure of the liquid propellant, the propellant rapidly vaporisesleaving a fast moving cloud of very fine particles of the drugformulation. This cloud of particles is directed into the nose or mouthof the patient by a channelling device such as a cylinder or open-endedcone.

Concurrently with the activation of the aerosol dose-metering valve, thepatient inhales the drug particles into the lungs or nasal cavity.Systems of dispensing drugs in this way are known as “metered doseinhalers” (MDIs). See Peter Byron, Respiratory Drug Delivery, CRC Press.Boca Raton, Fla. (1990) for a general background on this form oftherapy.

Patients often rely on medication delivered by MDIs for rapid treatmentof respiratory disorders, which are debilitating and in some cases evenlife threatening. Therefore, it is essential that the prescribed dose ofaerosol medication delivered to the patient consistently meets thespecifications claimed by the manufacturer and meets the requirements ofregulatory authorities. That is, every dose in the can must be deliveredwithin the same close tolerances.

A problem which can exist with drug delivery devices such as MDIs isdeposition of medicament, or the solid component from a suspension of aparticulate product in a liquid propellant, onto the internal surfacesof the device which occurs after a number of operation cycles and/orstorage. A reduction in the efficacy of the device may occur. Depositionof the product also reduces the amount of active drug available to bedispensed to the patient and markedly reduces the uniformity of the dosedispensed during the lifetime of the device.

Drug deposition and adherence and dose uniformity may be greater withsuspension formulations comprising hydrofluoroalkane propellants, forexample, 1,1,1,2-tetrafluoroethane (HFA134a) and1,1,1,2,3,3,3-n-heptafluoropropane (HFA227), which have been developedas ozone friendly replacements of chlorofluorocarbons such as P11, P114and P12.

Some conventional devices rely on the dispenser being shaken, to agitatethe liquid propellant and product mixture therein, in an attempt tore-suspend at least a portion of the deposited medicament. While in somecases this remedy can be effective within the body of the drug containeritself, it may not be effective for particles deposited on the innersurface(s) of other MDI components, such as the metering valve.

Canadian patent application 2130867 describes a metered dose inhalercontaining an aerosol formulation in which the internal walls of themetal canister are coated with a cross-linked plastics coating.Polytetrafluoroethylene (PTFE) and perfluoroethylenepropylene (FEP) arespecifically mentioned as suitable coating materials

UK patent application GB-A-2,328,932 discloses the use of a liner of amaterial such as fluoropolymer, ceramic or glass to line a portion ofthe wall of the metering chamber in a metering valve of an MDI. Althoughthis alleviates the problem of deposition in these types of dispensers,it does require the re-design or modification of mouldings and mouldtools for producing the valve members to allow for insertion of theliner.

SUMMARY OF THE INVENTION

It is therefore an aim of the present invention to provide a highlyfluorinated, reproducible coating which prevents or inhibits adhesion ofdrug particles to the internal surfaces of the canister and/or valvecomponents of a medicament dispenser, for example an MDI.

It is a further aim of the present invention to provide a coating withreduces moisture ingress into a medicament formulation, for example apharmaceutical aerosol formulation, reduces drug absorption into theinternal surface, especially when of rubber, and reduces extractablesleached out from the internal surface, especially when of plastics andrubber components.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, in a first aspect, the invention provides a dispenser fordispensing a medicament comprising a canister for housing the medicamentand a fluid propellant therefor and a drug-dispensing valve wherein oneor more of the internal surfaces of the canister and/or valve comprisesa fluorinated coating prepared from plasma polymerisation of one or morefluorinated monomers selected from the group consisting of CH₂FCF₃ andC₃F_(6.)

In a first embodiment, the coating is prepared from plasmapolymerisation of a CH₂FCF₃ monomer.

In a second embodiment, the coating is prepared from plasmapolymerisation of a C₃F₆ monomer.

Suitably, the fluorinated coating has a fluorine/carbon atomic ratio ofgreater than 10% about 1.0 and preferably greater than about 1.2, whenmeasured by Electronic Spectroscopy for Chemical Analysis (ESCA), alsoreferred to as X-ray photo spectroscopy (XPS).

Suitably, the fluorinated coating comprises greater than about 10% CF₂units and greater than about 10% CF₂CF units, the CF₂ and CF₂CF unitsbeing present either as part of a Teflon moiety or as a separate moiety.The percentage of CF₂ and CF₂CF units may be measured using ESCA.

Suitably, the surface energy of the coating gives a contact angle ofgreater than about 80 degrees, preferably greater than about 90 degrees.The term “contact angle” is the angle between a liquid water droplet andthe coated surface of the canister/valve at the liquid/solid interfaceas measured in ambient conditions, i.e. at a temperature of 20° C. (±5°C.) and a relative humidity of 50% (±20%). The contact angle may bemeasured on a coating deposited on a flat polybutylene terephthalate(PBT) substrate surface in accordance with the invention.

The thickness of the fluorinated coating is in the range of about 1 toabout 200 nm, suitably about 10 to 100 nm, and preferably about 20 to 80nm.

In one embodiment, one or more internal surfaces of the canistercomprise the fluorinated coating of the invention. In addition, oralternatively, one or more internal surfaces of the valve may comprisethe fluorinated coating of the invention.

Any parts of the canister or valve which contact the pharmaceuticalaerosol suspension may be coated with the fluorinated coating of theinvention. The fluorinated coating reduces or eliminates the tendencyfor medicament particles to adhere to such component surfaces. Where thevalve part is a movable part (e.g. the valve stem) the coating alsoreduces the friction between that part and an adjacent part of the valve(e.g. the stem seal).

As known by a person skilled in the art, the drug-dispensing valvesuitably comprises a number of components or parts. All of these may,independently of the other components, be coated with a fluorinatedcoating as hereinbefore defined. Component parts of the valve which maybe coated include, but are not limited to, the metering chamber, valvestem, the upper and lower stem seals, neck gasket, spring, body, and thering.

In one aspect herein, the valve stem is provided with the coating of theinvention to reduce its frictional contact properties, and the need forany further stem lubricant such as silicone oil is reduced oreliminated. Reducing frictional contact can be particularly advantageouswhere the valve is employed in a dispenser for both suspension andsolution medicament formulations.

In a further aspect, one or more internal surfaces of the meteringchamber are provided with a fluorinated coating according to the presentinvention.

In a still further aspect, one or more component parts selected from thegroup consisting of the upper and lower stem seals, neck gasket, spring,body, and ring are provided with a fluorinated coating according to thepresent invention.

In another aspect, the invention provides a drug-dispensing valve foruse in a dispenser for dispensing a medicament in a fluid propellant,wherein one or more of the internal surfaces of said valve comprise afluorinated coating prepared from plasma polymerisation of a fluorinatedmonomer selected from the group consisting of CH₂FCF₃ and C₃F₆.

In a further aspect, the invention provides a canister for housing themedicament in a fluid propellant, wherein one or more of the internalsurfaces of said canister comprise a fluorinated coating prepared fromplasma polymerisation of a fluorinated monomer selected from the groupconsisting of CH₂FCF₃ and C₃F₆.

The dispenser and/or drug-dispensing valve and/or canister ashereinbefore defined may be incorporated as part of a “metered doseinhaler” (“MDI” for short) for dispensing a medicament in a fluidpropellant under pressure. The term “MDI” means a unit comprising acanister, a ferrule covering the mouth of the canister, a drug meteringvalve situated in the ferrule, a metering chamber and a suitablechannelling device into which the canister is fitted. The relation ofthe parts of a typical MDI is illustrated in U.S. Pat. No. 5,261,538,the content of which is hereby incorporated herein by reference. Inanother aspect, the invention provides a metered dose inhaler fordispensing a medicament in a fluid propellant, comprising a dispenserand/or a drug-dispensing valve and/or a canister as defined above and amedicament channelling device, such as an actuator.

Optionally, moisture-absorbing means is further comprised within thedispenser and/or drug-dispensing valve and/or canister and/or metereddose inhaler of the invention as a component thereof. Examples ofmoisture absorbing means suitable for use with the present invention aredisclosed in co-pending UK Patent Application 0116891.3, the content ofwhich is hereby incorporated herein by reference.

The coating applied to one or more internal surfaces of the canisterand/or valve is prepared from a plasma generated substantially from afluorinated monomer selected from the group consisting of CH₂FCF₃ andC₃F₆. Alternatively, the fluorinated monomer selected from the groupconsisting of CH₂FCF₃ and C₃F₆ may be co-polymerised with one or moreadditional non-fluorinated monomers. Suitable copolymers comprise from0.5 to 99.5% by weight, preferably from 0.7 to 85% by weight, offluorinated monomer. In general the preference is to use anon-fluorinated monomer that forms the basic building block (monomer) ofthe substrate polymer or elastomer to be coated. For example, ifpolybutylene terephthalate (PBT) is the is substrate to be coated, themonomer used in producing PBT, dimethyl terephthalate, can be used inconjunction with the fluorinated monomer. Similarly, if the substrate isacetal, then CH₂O can be used. In general, irrespective of the substratematerial, when fluorinated coatings are produced using a plasma process,it is desirable to use basic hydrocarbon monomers, including, but notlimited to, CH₄, C₂H₆, C₂H₄, N₂, O₂, H₂, C₃COO(C₆H₆)COOCH₃, HO(CH₂)₂OH,C₃H₃N and C₄H₆ in conjunction with the fluorinated monomer.

The ratio of the gas flow rate of the fluorinated monomer to thenon-fluorinated monomer can be continuously varied during the course ofthe plasma coating process. In general, in order to obtain superioradhesion, this ratio can be low or the monomer gas can be rich in thenon-fluorinated species at the start of the process. This ratio can becontinuously increased and towards the end of the process it ispreferable to use only the fluorinated monomer in order to obtain afluorine rich surface in the top layers of the coating.

The fluorinated coating of the invention is prepared using a plasmapolymerisation process, suitably a RF plasma polymerisation processoperating at a frequency of 2 MHz to 200 MHz; suitably 13.56 MHz, 27.12MHz and 40.68 MHz; and preferably 13.56 MHz. The coating processtypically occurs under vacuum. The components to be coated are placedinside a rotating chamber, the chamber subsequently being evacuated. Thefluorinated monomer (and optionally additional monomeric material) isintroduced into the chamber, suitably at ambient temperature, and at acontrolled and predetermined flow rate. The monomer gas(es) is ignitedand dissociates into plasma within the chamber. The energy in thechamber is maintained for a given time at a chosen power setting. Duringplasma polymerisation electrode temperatures can typically increase fromabout 20° C. to about 100° C. A cooling system of the electrode is usedto minimise the temperature increase. At the end of the treatment theplasma is extinguished, the chamber flushed with air or argon and thecoated products retrieved. During the polymerisation process, a thinlayer of plasma polymer will be bonded to the canister and/or valvecomponent. The polymerisation process time may only be minutes, forinstance 30 minutes or less, or as long as several hours, depending onthe operating conditions etc., as will be understood by the skilledreader in the art.

Accordingly, a further aspect of the invention provides a process forcoating one or more of the internal surfaces of the canister and/orvalve component with a fluorinated coating, said process comprising thesteps of (i) placing the canister and/or valve component to be coated ina chamber, (ii) evacuating the chamber, (iii) feeding the fluorinatedmonomer selected from the group consisting of monomer CH₂FCF₃ and C₃F₆into the chamber, (iv) applying sufficient power to generate a plasma,(v) igniting the plasma, (vi) extinguishing any unreacted plasma, and(vii) flushing the chamber.

One or more additional non-fluorinated monomers may also be fed into thechamber. Suitably, the ratio of fluorinated to non-fluorinated gas flowrate is continuously varied during the process. More suitably, the ratioof fluorinated to non-fluorinated gas flow rate is increased during theprocess. Preferably, the monomer gas is pure non-fluorinated monomer atthe start of the process and pure fluorinated monomer at the end of theprocess.

The effectiveness of the fluorinated coating of the invention may dependon the operating conditions of the plasma reactor. The operatingparameters, which can be varied, include: power (W), gas pressure(mTorr), gas flow (cc/min), tumbler speed (rpm), temperature (° C.) andthe number of components in the chamber.

Suitably, the reactor operates at a power of between 50 W and 450 W,suitably 75 W and 300 W and preferably about 200 W.

Suitably, the reactor operates at a gas pressure of less than or equalto about 70 mTorr.

Suitably, the reactor operates at a gas flow of between 50 cc/min and200 cc/min, suitably between 75 cc/min and 100 cc/min.

Suitably, the reactor operates at a tumbler speed of between 1 and 15rpm, suitably at about 3 rpm or 8 rpm.

Suitably, the temperature of the electrode increases from 20° C. to 100°C.

The positioning of the components within the reactor may affect theeffectiveness of the coating. The components to be coated should bepositioned within the primary plasma in the reactor (inside the glow ofthe plasma). In order to obtain a uniform coating on all the components,the components should be evenly distributed in the reactor and thenrotated.

Suitably, to improve adhesion of the fluorinated coating to the internalsurfaces, the surfaces to be coated may be subjected to a pre-treatmentprocedure to remove any surface contamination and/or to activate thesurface. Accordingly, a further aspect of the invention provides adispenser for dispensing a medicament in a fluid propellant, thedispenser comprising a canister for housing the medicament and a drugdispensing valve, wherein one or more of the internal surfaces of thecanister and/or valve are subjected to a pre-treatment step to removesurface contamination and/or to activate the surface prior to providinga fluorinated coating as hereinbefore described. The pre-treatment stepmay be carried out by for example plasma treatment of the componentswith an etching gas such as oxygen or a neutral gas such as argon.Preferably, the gas is argon to avoid damage to the substrate. In theprocess, radicals react with the plastic or metal substrate; for examplethe component is exposed to a low pressure argon plasma environmentgenerating polar groups on the component's surface. Such polar groupsare more conducive to bonding with the fluorine-containing plasmacoating to be applied.

The pre-treatment step, for example with argon, could be carried outunder a range of conditions and duration. However, the followingconditions provide a satisfactory pre-treatment for a PBT substrate: runtime 5 minutes; power 300 W; gas pressure 80 mTorr; gas flow 150 cc/min;tumbler speed 3 rpm or 8 rpm. It should be noted, however, that theinvention is not limited to these conditions and that any set ofconditions used for a pre-treatment step is within the scope of theinvention. The pre-treatment process is dependent on the material to betreated.

The metered dose inhalers may be prepared by methods known in the art,for example as disclosed in Byron supra and U.S. Pat. No. 5,345,980, thecontent of each of which is hereby incorporated herein by reference.

Suitably, the entire valve or one or more of the valve components aremade of a non-metal material. Suitable non-metals for use in the valveinclude pharmacologically resilient polymers such as acetal, polyamide(e.g. Nylon®), polycarbonate, polyester (e.g. polybutylene terephthalate(PBT)), fluorocarbon polymer (e.g. Teflon®) or a combination of thesematerials. Additionally, seals and “O” rings of various materials (e.g.,nitrile rubbers, polyurethane, acetyl resin, fluorocarbon polymers), orother elastomeric materials, for example EPDM, and thermoplasticelastomer or chloroprene, are employed in and around the valve.Alternatively, the valve is made of metal, for example stainless steel,aluminium, copper, tin plate and any alloys thereof.

The valve can have any suitable configuration. Metal and non-metal partscan be combined to optimise the performance of the valve.

Conventionally, the canisters and caps for use in MDIs are made ofaluminium or an alloy of aluminium although other metals not affected bythe drug formulation, such as stainless steel, an alloy of copper, ortin plate, may be used. An MDI canister may also be fabricated fromglass or plastics. Preferably, however, the MDI canisters and capsemployed in the present invention are made of aluminium or an alloythereof.

The canister, when in use, is a pressurised container comprising a vial(preferably metal, more preferably aluminium) having a metering valvedisposed therein. Since the canister is preferably part of an MDI, themetering valve design is typically a function of providing apredetermined dosage or amount of the drug contained within thepressurised container to a user.

The valve typically comprises a valve body having an inlet port throughwhich the pharmaceutical aerosol formulation may enter said valve body,an outlet port through which the pharmaceutical aerosol may exit thevalve body and an open/close mechanism by means of which flow throughsaid outlet port is controllable.

The valve may be a slide valve wherein the open/close mechanismcomprises a sealing ring and receivable by the sealing ring a valve stemhaving a dispensing passage, the valve stem being slidably movablewithin the ring from a valve-closed to a valve-open position in whichthe interior of the valve body is in communication with the exterior ofthe valve body via the dispensing passage.

The metering volumes are typically from 25 to 100 μl, such as 50 μl or63 μl. Suitably, the valve body defines a metering chamber for meteringan amount of medicament formulation and an open/close mechanism by meansof which the flow through the inlet port to the metering chamber iscontrollable. Preferably, the valve body has a sampling chamber incommunication with the metering chamber via a second inlet port, saidinlet port being controllable by means of an open/close mechanismthereby regulating the flow of medicament formulation into the meteringchamber.

The valve may be a metering valve in which the valve body has a meteringchamber, a sampling chamber and therebetween a second sealing ringwithin which the stem is slidably movable, the valve stem having atransfer passage such that in the valve-closed position the dispensingpassage is isolated from the metering chamber and the metering chamberis in communication with the sampling chamber via the transfer passage,and in the valve-open position the dispensing passage is incommunication with the metering chamber and the transfer passage isisolated from the metering chamber.

The valve may also comprise a ‘free flow aerosol valve’ having a chamberand a valve stem extending into the chamber and movable relative to thechamber between dispensing and non-dispensing positions. The valve stemhas a configuration and the chamber has an internal configuration suchthat a metered volume is defined therebetween and such that duringmovement between non-dispensing and dispensing positions the valve stemsequentially: (i) allows free flow of aerosol formulation into thechamber, (ii) defines a closed metered volume for pressurised aerosolformulation between the external surface of the valve stem and internalsurface of the chamber, and (iii) moves with the closed metered volumewithin the chamber without decreasing the volume of the closed meteredvolume until the metered volume communicates with an outlet passagethereby allowing dispensing of the metered volume of pressurised aerosolformulation. A valve of this type is described in U.S. Pat. No.5,772,085, the content of which is hereby incorporated herein byreference.

The valve may also have a structure and action similar to those aerosolvalves described in European Patent Application No. EP-A-870,699 and PCTPatent Application No. WO99/36334, the content of each of which ishereby incorporated herein by reference.

The sealing ring and/or gasket may be formed by cutting a ring from asheet of suitable material. Alternatively, the sealing ring and/orgasket may be formed by a moulding process such as an injectionmoulding, a compression moulding or a transfer moulding process.

Typically, the sealing ring and/or second sealing ring and/or gasketcomprise an elastomeric material. The ring is typically resilientlydeformable.

The elastomeric material may either comprise a thermoplastic elastomer(TPE) or a thermoset elastomer, which may optionally be cross-linked.The sealing ring and/or gasket may also comprise a thermoplasticelastomer blend or alloy in which an elastomeric material is dispersedin a thermoplastic matrix. The elastomers may optionally additionallycontain conventional polymer additives. Such additives include but arenot limited to processing aids, colorants, tackifiers, lubricants,silica, talc, or processing oils such as mineral oil in suitableamounts.

Suitable thermoset rubbers include butyl rubbers, chloro-butyl rubbers,bromo-butyl rubbers, nitrile rubbers, silicone rubbers, fluorosiliconerubbers, fluorocarbon rubbers, polysulphide rubbers, polypropylene oxiderubbers, isoprene rubbers, isoprene-isobutene rubbers, isobutylenerubbers or neoprene (polychloroprene) rubbers.

Suitable thermoplastic elastomers comprise a copolymer of about 80 toabout 95 mole percent ethylene and a total of about 5 to about 20 molepercent of one or more comonomers selected from the group consisting of1-butene, 1-hexene, and 1-octene as known in the art. Two or more suchcopolymers may be blended together to form a thermoplastic polymerblend.

Another suitable class of thermoplastic elastomers are thestyrene-ethylene/butylene-styrene block copolymers. These copolymers mayadditionally comprise a polyolefin (e.g. polypropylene) and a siloxane.

Thermoplastic elastomeric material may also be selected from one or moreof the following: polyester rubbers, polyurethane rubbers, ethylenevinyl acetate rubber, styrene butadiene rubber, copolyether ester TPE,olefinic TPE, polyester amide TPE and polyether amide TPE.

Other suitable elastomers include ethylene propylene diene rubber(EPDM). The EPDM may be present on its own or present as part of athermoplastic elastomer blend or alloy, e.g. in the form of particlessubstantially uniformly dispersed in a continuous thermoplastic matrix(e.g. polypropylene or polyethylene). Commercially availablethermoplastic elastomer blend and alloys include the SANTOPRENE™elastomers. Other suitable thermoplastic elastomer blends includebutyl-polyethylene (e.g. in a ratio ranging between about 2:3 and about3:2) and butyl-polypropylene.

Typically, the sealing ring and/or the second sealing ring and/or gasketadditionally comprises lubricant material. Suitably, the sealing ringand/or the second sealing ring and/or gasket comprises up to 30% byweight, preferably from 5 to 20% by weight, of lubricant material.

In addition, the stem may also comprise lubricant material. Suitably,the valve stem comprises up to 30%, preferably from 5 to 20% lubricantmaterial by weight.

The term ‘lubricant’ herein means any material that reduces frictionbetween the valve stem and seal. Suitable lubricants include siliconeoil or a fluorocarbon polymer such as polytetrafluoroethane (PTFE) orfluoroethylene propylene (FEP).

Lubricant can be applied to the stem, stem gaskets or ferrule by anysuitable process including coating and impregnation, such as byinjection or by adding a reservoir of lubricant, which provides aconstant supply of lubricant throughout the life of the product.

In medical use the canisters in accordance with the invention contain apharmaceutical aerosol formulation comprising a medicament and afluorocarbon or hydrogen-containing chlorofluorocarbon propellant.

Suitable propellants include, for example, C₁₋₄hydrogen-containingchlorofluorocarbons such as CH₂ClF, CClF₂CHClF, CF₃CHClF, CHF₂CClF₂,CHClFCHF₂, CF₃CH₂Cl and CClF₂CH₃; C₁₋₄hydrogen-containing fluorocarbonssuch as CHF₂CHF₂, CF₃CH₂F, CHF₂CH₃ and CF₃CHFCF₃; and perfluorocarbonssuch as CF₃CF₃ and CF₃CF₂CF₃.

Where mixtures of the fluorocarbons or hydrogen-containingchlorofluorocarbons are employed they may be mixtures of theabove-identified compounds or mixtures, preferably binary mixtures, withother fluorocarbons or hydrogen-containing chloro-fluorocarbons forexample CHClF₂, CH₂F₂ and CF₃CH₃. Preferably a single fluorocarbon orhydrogen-containing chlorofluorocarbon is employed as the propellant.Particularly preferred as propellants are C₁₋₄hydrogen-containingfluorocarbons such as 1,1,1,2-tetrafluoroethane (CF₃CH₂F) and1,1,1,2,3,3,3-heptafluoro-n-propane (CF₃CHFCF₃) or mixtures thereof.

The pharmaceutical formulations for use in the canisters of theinvention contain no components that provoke the degradation ofstratospheric ozone. In particular the formulations are substantiallyfree of chlorofluorocarbons such as CCl₃F, CCl₂F₂ and CF₃CCl₃.

The propellant may additionally contain a volatile adjuvant such as asaturated hydrocarbon for example propane, n-butane, isobutane, pentaneand isopentane or a dialkyl ether for example dimethyl ether. Ingeneral, up to 50% w/w of the propellant may comprise a volatilehydrocarbon, for example 1 to 30% w/w. However, formulations which arefree or substantially free of volatile adjuvants are preferred. Incertain cases, it may be desirable to include appropriate amounts ofwater, which can be advantageous in modifying the dielectric propertiesof the propellant.

The invention is particularly useful with propellants (includingpropellant mixtures) which are more hygroscopic than P11, P114 and/orP12 such as HFA-134a and HFA-227.

A polar co-solvent such as C₂₋₆ aliphatic alcohols and polyols e.g.ethanol, isopropanol and propylene glycol, preferably ethanol, may beincluded in the drug formulation in the desired amount to improve thedispersion of the formulation, either as the only excipient or inaddition to other excipients such as surfactants. Suitably, the drugformulation may contain 0.01 to 30% w/w based on the propellant of apolar co-solvent e.g. ethanol, preferably 0.1 to 20% w/w e.g. about 0.1to 15% w/w. In aspects herein, the solvent is added in sufficientquantities to solubilise a part of, or all of, the medicament component,such formulations being commonly referred to as solution formulations.

A surfactant may also be employed in the aerosol formulation. Examplesof conventional surfactants are disclosed in EP-A-372,777, the contentof which is hereby incorporated herein by reference. The amount ofsurfactant employed is desirable in the range 0.0001% to 50% weight toweight ratio relative to the medicament, in particular, 0.05 to 5%weight to weight ratio.

The final aerosol formulation desirably contains 0.005-10% w/w,preferably 0.005 to 5% w/w, especially 0.01 to 1.0% w/w, of medicamentrelative to the total weight of the formulation.

Medicaments, which may be administered in the aerosol formulations,include any drug useful in inhalation therapy. The dispenser of theinvention is in one aspect suitable for dispensing medicament for thetreatment of respiratory disorders such as disorders of the lungs andbronchial tracts including asthma and chronic obstructive pulmonarydisorder (COPD). In another aspect, the invention is suitable fordispensing medicament for the treatment of a condition requiringtreatment by the systemic circulation of medicament, for examplemigraine, diabetes, pain relief e.g. inhaled morphine.

Accordingly, in one aspect, there is provided the use of a dispenser orMDI according to the invention for the treatment of a respiratorydisorder, such as asthma and COPD. Alternatively, the present inventionprovides a method of treating a respiratory disorder such as, forexample, asthma and COPD, which comprises administration by inhalationof an effective amount of an aerosol formulation as herein describedfrom a dispenser or MDI of the present invention.

A further aspect of the invention provides the use of a dispenser or MDIaccording to the invention for the treatment of a condition requiringthe systemic circulation of a medicament, such as, for example,migraine, diabetes, chronic pain. Alternatively, the present inventionprovides a method of treating a condition requiring the systemiccirculation of medicament, such as, for example migraine, diabetes andchronic pain, which comprises administration by inhalation of aneffective amount of an aerosol formulation as herein described from adispenser or MDI or the present invention.

Appropriate medicaments may thus be selected from, for example,analgesics, e.g., codeine, dihydromorphine, ergotamine, fentanyl ormorphine; anginal preparations, e.g., diltiazem; antiallergics, e.g.,cromoglycate (e.g. as the sodium salt), ketotifen or nedocromil (e.g. asthe sodium salt); antiinfectives e.g., cephalosporins, penicillins,streptomycin, sulphonamides, tetracyclines and pentamidine;antihistamines, e.g., methapyrilene; anti-inflammatories, e.g.,beclomethasone (e.g. as the dipropionate ester), fluticasone (e.g. asthe propionate or furoate ester), flunisolide, budesonide, rofleponide,mometasone (e.g. as the furoate ester), ciclesonide, triamcinolone (e.g.as the acetonide) or6α,9α-difluoro-11β,-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl)ester; antitussives, e.g.,noscapine; bronchodilators, e.g., albuterol (e.g. as free base orsulphate), salmeterol (e.g. as xinafoate), ephedrine, adrenaline,fenoterol (e.g. as hydrobromide), formoterol (e.g. as fumarate),isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine,pirbuterol (e.g. as acetate), reproterol (e.g. as hydrochloride),rimiterol, terbutaline (e.g. as sulphate), isoetharine, tulobuterol or4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)propyl]sulfonyl]ethyl]amino]ethyl-2(3H)-benzothiazolone;adenosine 2a agonists, e.g.2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol(e.g. as maleate); α₄ integrin inhibitors e.g.(2S)-3-[4-({[4-(aminocarbonyl)-1-piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy)acetyl]amino}pentanoyl)amino]propanoicacid (e.g. as free acid or potassium salt), diuretics, e.g., amiloride;anticholinergics, e.g., ipratropium (e.g. as bromide), tiotropium,atropine or oxitropium; hormones, e.g., cortisone, hydrocortisone orprednisolone; xanthines, e.g., aminophylline, choline theophyllinate,lysine theophyllinate or theophylline; therapeutic proteins andpeptides, e.g., insulin or glucagon; vaccines, diagnostics, and genetherapies. It will be clear to a person skilled in the art that, whereappropriate, the medicaments may be used in the form of salts, (e.g., asalkali metal or amine salts or as acid addition salts) or as esters(e.g., lower alkyl esters) or as solvates (e.g. hydrates) to optimisethe activity and/or stability of the medicament.

Preferred medicaments are selected from albuterol, salmeterol,fluticasone propionate and beclomethasone dipropionate and salts orsolvates thereof, e.g., the sulphate of albuterol and the xinafoate ofsalmeterol.

Medicaments can also be delivered in combinations. Preferredformulations containing combinations of active ingredients containsalbutamol (e.g., as the free base or the sulphate salt) or salmeterol(e.g., as the xinafoate salt) or formoterol (e.g. as the fumarate salt)in combination with an anti-inflammatory steroid such as abeclomethasone ester (e.g., the dipropionate) or a fluticasone ester(e.g., the propionate) or budesonide. A particularly preferredcombination is a combination of fluticasone propionate and salmeterol,or a salt thereof (particularly the xinafoate salt). A furthercombination of particular interest is budesonide and formoterol (e.g. asthe fumarate salt).

Particularly preferred formulations for use in the canisters of thepresent invention comprise a medicament and a C₁₋₄ hydrofluoroalkaneparticularly 1,1,1,2-tetrafluoroethane and1,1,1,2,3,3,3-n-heptafluoropropane or a mixture thereof as propellant.

Conventional bulk manufacturing methods and machinery well known tothose skilled in the art of pharmaceutical aerosol manufacture may beemployed for the preparation of large scale batches for the commercialproduction of filled canisters. Thus, for example, in one bulkmanufacturing method a metering valve is crimped onto an aluminium canto form an empty canister. The particulate medicament is added to acharge vessel and liquefied propellant is pressure filled through thecharge vessel into a manufacturing vessel. The drug suspension is mixedbefore re-circulation to a filling machine and an aliquot of the drugsuspension is then filled through the metering valve into the canister.Typically, in batches prepared for pharmaceutical use, each filledcanister is check-weighed, coded with a batch number and packed into atray for storage before release testing.

Each filled canister is conveniently fitted into a suitable channellingdevice prior to use to form a metered dose inhaler for administration ofthe medicament into the lungs or nasal cavity of a patient. Suitablechannelling devices comprise for example a valve actuator and acylindrical or cone-like passage through which medicament may bedelivered from the filled canister via the metering valve to the nose ormouth of a patient e.g. a mouthpiece actuator. Metered dose inhalers aredesigned to deliver a fixed unit dosage of medicament per actuation or“puff”, for example in the range of 2 to 5000 microgram medicament perpuff.

Administration of medicament may be indicated for the treatment of mild,moderate or severe acute or chronic symptoms or for prophylactictreatment. It will be appreciated that the precise dose administeredwill depend on the age and condition of the patient, the particularparticulate medicament used and the frequency of administration and willultimately be at the discretion of the attendant physician. Whencombinations of medicaments are employed the dose of each component ofthe combination will in general be that employed for each component whenused alone. Typically, administration may be one or more times, forexample from 1 to 8 times per day, giving for example 1,2,3 or 4 puffseach time. Each valve actuation, for example, may deliver 5 μg, 50 μg,100 μg, 200 μg or 250 μg of a medicament. Typically, each filledcanister for use in a metered dose inhaler contains 60, 100, 120 or 200metered doses or puffs of medicament; the dosage of each medicament iseither known or readily ascertainable by those skilled in the art.

For the avoidance of doubt, the use herein of the term “about” inreference to the value(s) of certain parameters is meant to include theexact value of that parameter, e.g. a reference to the relative amountof a material being “about Xg by weight” encompasses the relative amountbeing exactly Xg by weight.

1. A dispenser for dispensing a medicament comprising a canister forhousing the medicament and a fluid propellant therefor and adrug-dispensing valve wherein one or more of the internal surfaces ofthe canister and/or valve comprises a fluorinated coating prepared fromplasma polymerisation of one or more fluorinated monomers selected fromthe group consisting of CH₂FCF₃ and C₃F₆.
 2. A dispenser according toclaim 1, wherein the fluorinated coating is prepared from the plasmapolymerisation of CH₂FCF₃.
 3. A dispenser according to claim 1, whereinthe fluorinated coating is prepared from the plasma polymerisation ofC₃F₆.
 4. A dispenser according to claim 1, wherein the fluorinatedcoating has a fluorine/carbon atomic ratio of greater than about 1.0. 5.A dispenser according to claim 4, wherein the fluorine/carbon atomicratio is greater than about 1.2.
 6. A dispenser according to claim 1,wherein the fluorinated coating comprises greater than about 10% CF₂units.
 7. A dispenser according to claim 1, wherein the fluorinatedcoating comprises greater than about 10% CF₂CF units.
 8. A dispenseraccording to claim 1, wherein the fluorinated coating gives a contactangle of greater than about 80°.
 9. A dispenser according to claim 8,wherein the fluorinated coating gives a contact angle of greater thanabout 90°.
 10. A dispenser according to claim 1, wherein the fluorinatedcoating has a thickness in the range of about 1 to 200 nm.
 11. Adispenser according to claim 10, wherein the thickness is in the rangeof about 10 to 100 nm.
 12. A dispenser according to claim 1, wherein thefluorinated coating is provided on one or more internal surface of thecanister.
 13. A dispenser according to claim 1, wherein the fluorinatedcoating is provided on one or more internal surfaces of the valve.
 14. Adispenser according to claim 13, wherein the fluorinated coating isprovided on one or more internal surfaces of a metering chamber of thevalve.
 15. A dispenser according to claim 13, wherein the fluorinatedcoating is provided on a valve stem of the valve.
 16. A dispenseraccording to claim 13, wherein the fluorinated coating is provided onone or more valve component parts selected from the group consisting ofan upper stem seal, a lower stem seal, a neck gasket, a spring, a bodyand a ring.
 17. A dispenser according to claim 1, wherein thefluorinated coating is prepared from the plasma co-polymerisation of oneor more fluorinated monomers selected from the group consisting ofCH₂FCF₃ and C₃F₆ and one or more additional non-fluorinated monomers.18. A dispenser according to claim 17, wherein the one or moreadditional non-fluorinated monomers are selected from the groupconsisting of CH₄, C₂H₆, C₂H₄, N₂, O₂, H₂, C₃COO(C₆H₆)COOCH₃,HO(CH₂)₂OH, C₃H₃N and C₄H₆.
 19. A drug-dispensing valve for use in adispenser for dispensing a medicament in a fluid propellant, wherein oneor more internal surface of said valve comprises a fluorinated coatingprepared from plasma polymerisation of one or more fluorinated monomersselected from the group consisting of CH₂FCF₃ and C₃F₆.
 20. A canisterfor housing a medicament in a fluid propellant, wherein one or moreinternal surface of said canister comprises a fluorinated coatingprepared from plasma polymerisation of one or more fluorinated monomersselected from the group consisting of CH₂FCF₃ and C₃F₆.
 21. A processfor coating one or more internal surfaces of a canister and/or valvecomponent with a fluorinated coating, said process comprising the stepsof (i) placing the component to be coated in a chamber, (ii) evacuatingthe chamber, (iii) feeding a fluorinated monomer selected from the groupconsisting of CH₂FCF₃ and C₃F₆ into the chamber, (iv) applyingsufficient power to generate a plasma, (v) igniting the plasma, (vi)extinguishing any unreacted plasma, and (vii) flushing the chamber. 22.A process according to claim 21, wherein one or more additionalnon-fluorinated monomers are fed into the chamber.
 23. A processaccording to claim 22, wherein the ratio of fluorinated tonon-fluorinated gas flow rate is continuously varied during the process.24. A process according to claim 22, wherein the ratio of fluorinated tonon-fluorinated gas flow rate is increased during the process.
 25. Aprocess according to claim 22, wherein the monomer gas is purenon-fluorinated monomer at the start of the process and pure fluorinatedmonomer gas at the end of the process.
 26. A process according to claim21, wherein the process is carried out at a power from 50 W to 450 W.27. A process according to claim 21, wherein the process is carried outat a gas pressure of less than or equal to 70 mTorr.
 28. A processaccording to claim 21, wherein the process is carried out at a gas flowrate from 50 cc/min to 200 cc/min.
 29. A process according to claim 21,wherein the process is carried out at a tumbler speed from 1 to 15 rpm.30. A process according to claim 21, wherein the process is carried outat a temperature from 20° C. to 100° C.
 31. A process according to claim21, wherein the plasma polymerisation process is carried out at a radiofrequency in the range of 2 MHz to 200 MHz.
 32. A process according toclaim 31, wherein the radio frequency is approximately 13.56 MHz.
 33. Aprocess according to claim 21 in which the plasma is maintained for aduration of 30 minutes, or substantially 30 minutes.
 34. A processaccording to claim 21, wherein said process comprises a pre-treatmentstep to remove surface contamination and/or activate the surface.
 35. Aprocess according to claim 34, wherein said pre-treatment step comprisesplasma treatment of the components with oxygen or argon.
 36. A dispenseraccording to claim 1 comprising a medicament in a fluid propellant underpressure, wherein the fluid propellant comprises a hydrofluoroalkane.37. A method of preventing drug deposition in a dispenser for dispensinga medicament in a fluid propellant under pressure having a canister forhousing the medicament and a drug-metering valve, the method comprisingthe use of a dispenser, a drug metering valve or a canister as claimedin claim
 1. 38. (canceled)
 39. A method of treating a respiratorydisorder, which comprises administration by inhalation of an effectiveamount of a medicament in a fluid propellant from a dispenser as claimedin claim
 1. 40. (canceled)
 41. A method of treating a conditionrequiring systemic circulation of a medicament, which comprisesadministration by inhalation of an effective amount of a medicament in afluid propellant from a dispenser as claimed in claim 1.